We have implicated the neuronal sortilin-related receptor gene (S0RL1) as a susceptibility gene for Alzheimer's disease (AD). S0RL1 is involved in intracellular sorting of APP, and under-expression of S0RL1 leads to over-expression of A and an increased risk of AD. Our preliminary studies suggest that at least two additional genes in the same sorting pathway play a role. The purpose of this study is to use functional genomics and genetic linkage and association analyses to identify additional causative genes in this pathway. The study will capitalize on 3 established cohorts; ADRC AD and control brains; Caribbean Hispanics from the population-based WHICAP project who have genome-wide screening; a cohort of Caribbean Hispanic families multiply affected by AD which has genome wide screening. Aim 1: To identify additional causative genes in the sortilin-related pathway through computational network reconstruction and gene expression profiling of pathologically defined AD cases and controls. Hypothesis 1: Besides S0RL1, additional genes in the sortilin pathway are involved in AD and will be differentially expressed in AD and control brains. Aim 2: To identify the specific causative variants in the candidate genes identified through Aim 1 by fine-mapping and linkage and association analyses in the epidemiological cohort of Caribbean Hispanics and the cohort of Caribbean Hispanic families. To further explore the mechanisms by which these variants act on AD by examining their association with age-of-onset of AD and AD endophenotypes (i.e. plasma A40 and A42 levels, memory). Hypothesis 2: Causative variants in the sortilin-related pathway that were identified through Aim 1 and are differentially expressed in AD and control brains will be associated with AD status in case control association analyses and family based linkage analyses. Hypothesis 3: Causative variants will be associated with differences in A40, A42 and memory. Aim 3: To confirm identified candidate genes through functional analyses (real-time PCR, siRNA suppression). Hypothesis 4: Causative genes in the sortilin pathway will be differentially expressed in real-time PCR of AD and control tissue. Suppression of siRNA will lead to changes in levels of APPs, A40 and A42. RELEVANCE: Pathways regulating protein sorting play a major role in Alzheimer's disease (AD). Our robust preliminary findings suggest that besides S0RL1, at least two additional genes in the sortilin pathway are involved. Mapping the additional causative factors in the sortilin pathway that are mechanistically involved in AD will help elucidate the etiology of AD and will identify targets for prevention, treatment and genetic testing.